Carbalkoxylation of organic compounds



Patented Sept. 17, 1946 CARBALKOXYLATION OF ORGAN IC' COMPOUNDS VernonH. Wallingford, Ferguson, and August H.

Homeyer, St. Louis, Mo., assignors to Mallinckrodt Chemical Works, St.Louis, Mo., a

corporation of Missouri No Drawing. Application February 20, 1941,Serial No. 379,828

14 Claims.

This invention relates to the carbalkoxylation of organic compounds, andwith respect to certain more specific features, to the introduction ofcarbalkoxy groups into ketones.

This application is a continuation-in-part of our copending applicationsSerial No. 287,001, filed July 28, 1939, Serial No. 374,254, filedJanuary 13, 1941, and Serial No. 375,614, filed January 23, 1941.

Among the several objects of the invention may' be noted the provisionof a general process for bringing about a carbalkoxylation of the typeindicated, which is characterized by its high yield, its inexpensive andreadily procurable reaction materials, and the facility with which itmay be carried out. Other objects will be in part obvious and in partpointed out hereinafter- The invention accordingly comprises the stepsand sequence of steps, and features of synthesis, analysis, ormetathesis, which will be exemplified in the processes and productshereinafter described, and the scope of the application of which will beindicated in the following claims.

While the process of the present invention provides primarily for theintroduction of a carbalkoxy group into a ketone, it also, in manyinstances, produces the carbalkoxylated product in the form of a highlyreactive metallo-derivative which readily lends itself to further stepsof synthesis. This metallo-compound may be then directly alkylated bythe well-known procedures, or if carbalkoxylation alone is desired themetallo-group may be replaced by hydrogen in the usual fashion. Themetal of such a group is usually and preferably one of the alkalimetals.

Broadly speaking, the process of the present invention comprises thecarbalkoxylation oi ketones through the interaction of a ketone, adialkyl carbonate and a metal alcoholate in the dialkyl carbonate, andpreferably in substantial excess, as the reaction medium. This may berepresented by the following equation:

where X is an organic residue, Y is the same or a difierent organicresidue and may be hydrogen,

R is the alkyl of the dialkyl carbonate, M'is an alkali metal, and R isthe radical of the alcoholate.

While the reaction is preferably carried out with a symmetrical dialkylcarbonate as shown in the equation, it can be carried out with anunsymmetrical dialkyl carbonate. In such cases,

a mixture of carbalkoxylated compounds and product alcohols may beformed.

The mechanism of the reaction involved in the process of the presentinvention has not yet been definitely established. The large excess ofdialkyl carbonate which is preferred, appears, however, to be animportant factor.

The reaction may be pushed to substantial completion by heating as itprogresses, to distill off the product alcohols (ROI-I and R'OH in theabove equation). In case the original metal alcoholate contains alcohol,such alcohol is likewise removed by this distillation procedure. Thisprocedure, while somewhat optional, is highly advantageous in itsimprovement in the yield of carbalkoxylated compound obtained.

When the intended use of the sodioor other alkali metal compound is thepreparation therefrom of an alkyl substituted compound,the'sodiocompound need not be recovered from the residue as such, butthe residue may be alkylated to form the alkylated compound which maythen be recovered from the reaction mixture. On theother hand, ifcarbalkoxylation alone is desired, the sodio-group, for example, may bereplaced by hydrogen by anysuitable method, for example, byacidification.

The following examples illustrate certain speciflc embodiments of thepresent invention, but are intended to be by way of example only:

" EXAMPLE .1

ACETOPHENONE Sodium ethylate and diethyl carbonate Sodium (4.6 g.) wasadded to anhydrous ethyl alcohol ml.) in a 500 ml, three-necked flaskarranged with a sealed stirrer, an oil bath, and a fractionating column.After the reaction was complete the excess alcohol was vacuum distilledout until only 8.5 g. of alcohol remained. The mixture was cooled anddiethyl carbonate (125 ml.) was added. The cake of sodium ethylate wasbroken up by stirring until an even. suspension resulted.

The mixture was stirred and cooled to 10 C. and acetophenone (24 g.) wasadded slowly during twenty minutes. The temperature was kept below 15 C.with an ice-water bath. Then the mixture was stirred at 15-20 C. forfifteen minutes and then at 40-50 C. for ten minutes. The alcoholpresent was then fractionally distilled out at mm. and a bathtemperature of 100 C. during 1.5 hours. The mixture was then cooled anddecomposed with acetic acid and water.

2-3 The oil was washed free of acid with water, dried, and fractionated.There was obtained a 59% (22.5 g.) yield of ethyl bensoylacetate,boiling point 138-144) C. at -6 mm., 11. 24/D 15251-1526 1. This productwas identified by reacting it with phenylhydrazine to produce 1,3-diphenylpyrazolone-B, which melted at 137-138 C.

EXAMPLE 2 Aonrornnnoma (Potassium butylate and dibutyl carbonate)Potassium (40 g.) was dissolved in ri-butyl aloe-- hol (300 ml.) anddistilled to dryness. The residue was heated at 120 C. and mm. pressureuntil :5

the potassium butylate was substantially free of alcohol. After cooling,di-n-butyl carbonate (700 ml.) was added and the reaction flask wasfitted with a stirrer, dropping funnel and fractionating column arrangedfor distillation at reduced pressure. The mixture in the flask wasstirred at 25 C. while acetophenone (123 g.) was added from the droppingfunnel during one hour. Then butyl alcohol was distilled out of thereaction mixture, the distillate being collected at about C. at 18 mm.pressure.

The reaction mixture was cooled and agitated with acetic acid (70 ml.)and ice l-G0 g.). The organic layer was separated, washed, and distilledat reduced pressure. After removal of the excess dibutyl carbonate andlow boiling material, the product, n-butyl benzoylacetate, distilled atabout 120-125 C. at 1 mm., and its index of refraction was about n 21/D1.5161 to 1.5185. The

yield was 106 g., or 48% of the theoretical based on 1 Wasrecrystallized from alcohol and melted at EXAMPLE 3 P-CHLOROACETOPHENONE p-Chloroac'etophenone (78 g.) and diethyl carbonate (500 ml.) wererefluxed under a packed column at 150 mm. pressure, while a solution ofsodium ethylate made from sodium metal (12 g.) and anhydrous alcohol(250 ml.) was added from a dropping funnel. Alcohol was distilled outsimultaneously and when no more was obtainable as distillate, thereaction mixture was cooled, acidified with acetic acid (35 ml.) andagitated with ice water. The organic layer was separated, washed, dried,and distilled.

After removal of the excess diethyl carbonate, the product, ethylp-chlorobenzoylacetate, distilled. at about 123-125 C. at 2 mm.pressure. Its index of refraction was 12 2l/D 1.54 11 to 1.5475. Theyield was 79.6 g., or 70% of the theoretical based onp-chloroacetophenone. A sample of the product was converted to thecopper salt by dissolving in alcohol and adding a saturated solution ofcopper acetate until no more precipitate formed. The green copper saltwas decomposed by shaking with ether and a solution of acetic acid, andthe ether layer was washed free of copper salts. Evaporation of thesolvent gave an oil which crystallized as large plates, and onrecrystallization from 60% alcohol, gave a pure product melting at37-40" C.

The identity of the product was established by converting a sample of itto 3-p-chlorophenyl-1- phenylpyrazolone5. A sample of the purified ester(23 g.), phenylhydrazine 1.1 ml.), alcohol 4 (2 ml.), and dilutehydrochloric acid (one drop), were heated together for one hour and thesolid which formed was recrystallized from alcohol'and sublimed in ahigh vacuum at about 14.0 C. It

melted at 161. C. and analysis gave 13.2% chlorine compared to thetheoretical calculated for C15H11ON2C1 01 13.1%.

EXAMPLE 4 P-Ms'rHYLAcs'roPHENoNE Potassium metal (13 g.) was dissolvedin npropyl alcohol ml.) in a 500 ml. threeneclied flask and the excessalcohol was distilled off. The residue was heated at 100 C. and. 30

mm. pressure until the potassium propylate was substantially free ofalcohol. After cooling, di-np'ropyl carbonate (250 ml.) was added to theresidue and the flask was fitted with a mechanical stirrer, drop-pingfunnel and fractionating column arranged for distillation at reducedpressure. The mixture in the flask was brought to refluxing un der apressure of 100 mm. and a solution of p-methylacetophenone (45 g.) inpropyl carbonate (50 ml.) was added from the dropping funnel during onehour? while prop-yl alcohol was ob tained simultaneously as distillateat the head of the column, boiling at about 47-51 C. at 108 mm. When nomore propyl alcohol was obtainable as distillatethe reaction'mixture wascooled and agitated with ice and acetic acid. The organic layer wasseparated, washed free of acid, dried, and fractionated. After removingthe excess dipropyl carbonate, the product, n prQpyl pi'nethylbenzoylacetate, distilled at -435? C. at 2 mm. pressure. Itsindex of refraction was aib'out n 20/D 1.5250. The yield was 47.8 g, or66% of the theoretical based on p-rnethylacetophenone.

The identity of the product was established by converting a sample of itto 3 p-tolyl isoxazo lone-5 by reaction with hydroxylaminehydrochloride. The product melted at 131-133" (3.

EXAMPLE 5 P-METHOXYACETOPHENONE Sodium (12 g.) was dissolved inanhydrous ethyl alcohol (256 ml.) in a 1 liter, three-necked flask. Theexcess alcohol was distilled off and the residue was heated at 160 C.and a pressure of about 29 mm. until the sodium ethylate wassubstantially free of alcohol. After cooling, diethyl carbonate (496ml.) was added and the'fiask was fitted to a fractionating columnarranged for a distillationat reduced pressure and equipped with amechanical stirrer and dropping funnel. The reaction mixture wasrefluxed under a pressure of mm. and a solution of p-methoxyacetophenone(75 g.) in diethyl carbonate (100 ml.) was added gradually from thedropping funnel during 1% hours, and simultaneously alcohol was removedas distillate at the head of the column. When no more alcohol wasobtainable as distillate the reaction mixture was cooled, acidified withacetic acid (35 Till.) and agitated with ice 'water. The organic layerseparated, dried over calcium chloride and distilled. After removal ofthe excess diethyl carbonate and some low boiling material, the product,ethyl p r'nethoxybenzoylacetate, distilled between C. at 4.5 and 147 C.at 2.5 mm. The yield was 55.8 g., or 50% of the theoretical based onp-methoxyacetophenone introduced.

The identity of the product was established by allowing a sample of itto react with hydroxylamine hydrochloride, yielding 3-(4-methoxyphenyl)-l soxaz'olone-5, which melted at 141-144 EXAMPLE 6 P-ETHOXYACETOPHENONEDiethyl carbonate (500 ml.) and p-ethoxyacetophenone (82 g.) were placedin a 1 liter, threenecked flask, fitted with a mechanical stirrer,

dropping funnel and packed fractionating column. The reaction mixturewas stirred, heated to refluxing, and a solution of sodium ethylate madefrom sodium (12 g.) and anhydrous ethyl alcohol (250 ml.) was addedslowly from the dropping funnel, while alcohol was removedsimultaneously as distillate at the head of the column. When no morealcohol was obtainable as distillate the reaction mixture was cooled andpoured onto a mixture of ice and hydrochloric acid. The organic layerwas separated, washed free of acid, dried over calcium chloride anddistilled until all diethyl carbonate had been removed.

Since the residue tended to decompose on heating under a pressure of 2mm., the product was purified by means of its copper salt. The residuewas mixed with alcohol (100 ml.) and treated with a saturated, aqueoussolution of copper acetate until no more precipitate formed. The greensolid was filtered off and washed with alcohol. It was decomposed with asolution of acetic acid in the presence of ether and the ether layer waswashed with water until free of copper. Evaporation of the ether yieldedan oil which solidified and was recrystallized from petroleum ether. Theproduct, ethyl p-ethoxybenzoylacetate, melted at 50-53 C., and aftersublimation of a sample in a high vacuum at 87 C., it melted at 53-54 C.The yield was 45 g., or 38% of the theoretical based onp-ethyoxyacetophenone. Analysis of the product gave 66.2% carbon and6.78% hydrogen, compared to the theoretical calculated for C13H1604 of66.06% carbon and 6.83% hydrogen.

The identity of the product was further established by converting asample to 3-(4-ethoxyphenyl) -isoxazoloneby reaction with hydroxylamine.A sample of the product (1 g.) was heated with hydroxylaminehydrochloride (1 g.), water (4 ml.), sodium acetate (2 g.), and alcohol(12 ml.) On cooling, a solid separated which was recrystallized twicefrom alcohol and dried. The 3-(4 ethoxyphenyl) isoxazolone 5 melted at135-136 C. and analysis for nitrogen gave 6.83% compared to thetheoretical calculated for C11H11O3N of 6.82%.

3-(4-ethoxyphenyl) -1-phenylpyrazolone-5 was prepared by heatingtogether a sample of the ester (2 g.), phenylhydrazine (2 ,ml.), alcohol(4 ml.) and dilute hydrochloric acid (one drop). A solid formed whichwas washed with 50% alcohol and recrystallized twice from alcohol. It

melted at 152-158 0., and analysis for nitrogen gave 9.98% compared tothe theoretical calculated for C17H1602N2 of 10.0%.

EXAMPLE 7 PROPIOPHENONE Sodium (18 g.) was dissolved in anhydrous ethylalcohol (350 m1.) and distilled to dryness. The residue was heated at130 C. at 20 mm. pressure until the sodium ethylate was substantiallyfree of alcohol. After cooling, diethyl carbonate proven to be ethylalphabenzoylpropionate. The

(500 ml.) was added and the reaction mixture was stirred and warmed atabout 60 C., while propiophenone (101 g.) was added slowly from adropping funnel. The flask was attached to a latter product distilled at-118 C. at 1 mm. and the index of refraction was n 25/D 1.5070 to1.5090. The yield was 56 g., or 37% of the theoretical. Its identity wasestablished by converting a sample to 4-methyl-3-phenyl-isoxazolone-5.,A portion of the ester (2 ml.) was combined with hydroxylaminehydrochloride (1.5 g.), sodium acetate (2.5 g.), water (5 ml.),'andalcohol (15 ml), and heated for one hour. Water (10 cc.) was added, thealcohol was boiled oil, and the residue was extracted with ether. Theether extract was dried and evaporated and the residue wasrecrystallized from petroleum ether. The product melted at 122124 C.

EXAMPLE 8 BUTYROPHENONE Sodium (18 g.) was dissolved in ethyl alcohol(350 ml.) and distilled to dryness. The residue was heated at C. at 20mm. until the sodium ethylate was substantially free of alcohol. Aftercooling, diethyl carbonate (600 ml.) was added and stirred at about 70C. while butyrophenone (111 g.) was added slowly from a dropping funnel.The reaction flask was attached to a fractionating column and as muchalcohol as possible was distilled out under a pressure of about 150 mm.The reaction mixture was cooled and agitated with ice and excesshydrochloric acid. The organic layer was separated, washed, dried, andfractionated. After all the diethyl carbonate had been removed, the oilyresidue weighed g. Fractionation gave two products. The material boilingat about 98-100 C. at.1.5 mm., n21.5/D 1.489, was ethylbutyrophenone-enol carbonate.

The material distilling at 118123 C. at 1.5 mm. was shown to be ethylalpha-benzoylbutyrate by converting a sample to 4-ethyl-3-phenyl-isoxazolone-5. A sample of the ester (2 ml.) was combined withhydroxylamine hydrochloride (1.5 g.), sodium acetate (2 g.), water (5ml.), and alcohol (10 ml.) and boiled. After most of the alcohol hadbeen driven off, water was added and the oil was extracted with ether.

The ether layer was dried, evaporated to a small volume, and the productwas crystallized by adding petroleum ether. The derivative melted at88-90 C.

EXAMPLE 9 DESOXYBENZOIN carbonate (50 ml.) was added during twentyminutes. The mixture was warmed to 50 C. and stirred for twenty minutes.Then the alcohol present was fractionally distilled off. After the bulkof .the alcohol was distilled of! rapidly it slowly continued to formand to be distilled out, and the operation was continued for a total ofthree hours at a bath temperature of 100 C. and a pressure of 120 mm.Then the mixture was cooled and decomposed with acetic acid and water.The organic layer was separated from the water layer and was washed freeof acid with dilute sodium carbonate solution and water and dried andthe diethyl carbonate was vacuum distilled out. From the residue therewas obtained by crystallization a yield of (2.5 g.) of ethylphenylbenzoylacetate, which melted at 90-91" C.

EXAMPLE DIBENZYL KETONE A mixture was made of sodium ethylate (13.6 g.),diethyl carbonate (125 ml.) and ethyl alcohol (8.5 g.); as described inExample 1. The mixture was stirred and cooled to C. and dibenzyl ketone(42 g.) was added during twenty minutes. After fifteen minutes morestirring the bath'was heated to a final temperature of EXAMPLE 11 METHYLBETA-NAPHTHYL KETONE A mixture was made of sodium ethylate (13.6 g.),diethyl carbonate (100 ml.), and ethyl alcohol (95 'g.), as described inExample 1. The mixture was cooled to 5 C. and stirred. During twentyminutes, at 5-10 C., a solution of methyl beta-naphthyl ketone (34 g.)in diethyl carbonate (50 ml.) was added. Then the mixture was heated to30 C. for fifteen minutes. Then the bath was heated to JO-100 C. and,during hour, 36 m1. of alcohol was fractionally distilled out at 120 mm.The mixture was cooled and worked up as in Example 1. After the solventwas off there was obtained an oil. This oil was taken up in ethylalcohol and a. water solulution of copper acetate was added until nomore green precipitate formed. This precipitate, recrystallized frombenzene, melted at 190-l92 C. The solid was suspended in water andacetic acid was added with shaking. The oil which formed was extractedwith ether. The ether solution was dried and the ether was evaporatedoff. From the residue there was obtained ethyl betanaphthoylacetate,melting V at 32-34 C. A phenylhydrazine derivative obtained from thisester melted at 117-118? C. [The yield of the ester was EXAMPLE 12Dmrmn. KETONE Sodium (9.2 g.) was added to anhydrous ethyl alcohol (200'ml.) in a 500 ml. three-necked flask arranged with a sealed stirrer, anoil bath, and a fractionating column. After the reaction was completethe excess alcohol was vacuum distilled out until onlyabout 25 g. ofalcohol remained. The mixture was cooled and diethyl stirred and Cooledto 15 C. and diethyl ketone The mixture was cooled and decomposed IAnalysis gave:

(34.4 e.) was added in ten minutes. The mixture was warmed to 30 C. andstirred for thirty minutes. The mixture was then warmed to 50-60 C. andstirred for one hour. All the alcohol present was then fractionallydistilled out during 1.5 hours at 120 mm. and a bath temperature of 100C. The mixture was cooled and decomposed with acetic acid and water. Theoil was washed free of acid with water, dried, and fractionated. Therewas obtained a 20% (12.5 g.) yield of ethylZ-methyl-3-keto-pentanoate,boiling point 103-106 C. at 32 mm. Thisproduct was identified by reacting it with phenylhydrazine to produce4-methyl-3-ethy1-1-phenylpyrazolone-5, which melted at 111-112 C.

EXAMPLE 13 METHYL ISOPROPYL KETONE excess diethyl carbonate an esterfraction boiling at 70-81 C. at 10 mm. and weighing 21.6 g., wasobtained. The product, dissolved in alcohol, gave a red color whentreated with a little ferric chloride solution, indicating the presenceof an enolic group. The product was identified as an ester of4-methyl-3-keto-pentanoic acid by converting a sample to3-isopropyl-l-phenylpyrazolone-5. A sample of the ester was treated withan equal volume of phenylhydrazine and allowed to stand. The solidformed was recrystallized from petroleum ether containing a littlealcohol, and then from a mixture of ether and petroleum ether. A samplesublimed in a high vacuum at C. and the sublimate melted at-8183 C.carbon 71.9%, hydrogen 7.0% and nitrogen 13.9%, compared to thetheoretical calculated for C12H14ON2 of carbon 71.2%, hy-

drogen 6.98% and nitrogen 13.81%.

EXAMPLE. 14

DI-N-PROPYL KETONE tilled out 15. cc. of distillate at 45-50" 0., headtemperature, consisting mostly of alcohol. The mixture was cooled anddecomposed with acetic acid and water. The oil was washed free of acidwith water, dried, and fractionated. There was obtained a 44% (34 g.)yield of ethyl 2-ethyl-3- keto-hexanoate, boiling point 126-127" C. at34 mm. n 31/1) 1.4224-1A226. This compound was identified by reacting itwith hydrazine to prepare 4-ethyl-3-propyl-pyrazolone-5, which melted at163-165 0.

EXAMPLE 15 METHYL ISOBUTYL KETONE A mixture was made of sodium ethylate(13.6 g.), diethyl carbonate (100 ml.), and ethyl alcohol (15 g.), asdescribed in Example 12. The mixture was stirred with the flask in abath at 10-15 C. and methyl isobutyl ketone (20 g.) was added duringtwenty minutes. The mixturewas then warmed to 30 C. for fifteen minutes.The bath was then warmed to 100 C. and the pressure arranged at 120 mm.and all the alcohol present was fractionally distilled out during 1.5hours. The mixture was worked up as in EX- ample 12. There was obtaineda 60% (18.5 g.) yield of ethyl 3-ket0-5-methyl-hexanoate, boiling point95-99 C. at 14 mm., n 24/D 14260-14270. This compound was identified byreacting it with phenyl-hydrazine to obtain 3-isobutyl-l-phenyl-pyrazolone-5, which melted at 107-108 C.

EXAMPLE 16 PINACOLONE Pinacolone (50 g.) and diethyl carbonate (300 ml.)were stirred mechanically and cooled to 2 C., while a paste ofalcohol-free sodium methylate (25 g.) in about an equal amount ofdiethyl carbonate was added slowly. The reaction was continued and theproduct worked up by the pro cedure described in Example 13. A portionof the distillate boiling at about 90 C. at 15 mm. was combined with anequal volume of phenylhydrazine, and on the following day the solidproduct was recrystallized from petroleum ether containing a littleanhydrous alcohol. The derivative was3-tert.-butyl-1-phenylpyrazolone-5, melting point 110-111 C., whichproved that the product obtained from the main reaction was an ester of4,4-dimethyl-3-keto-pentanoic acid.

EXAMPLE 17 METHYL N-AMYL KETONE Methyl n-amyl ketone (57 g.) and diethylcarbonate (500 ml.) were placed in a 1 liter, threenecked flask fittedwith a mechanical stirrer, dropping funnel and fractionating columnarranged for distillation at reduced pressure. The reactants werestirred and refluxed under a pressure of 100 mm.; while a solution ofsodium ethylate made from sodium metal (11.5 g.) and anhydrous alcohol(2'70 ml.) was added slowly from the dropping funnel. Alcohol wasremoved simultaneously as distillate at the head of the column at about38 C. at 100 mm. When no more alcohol was obtainable as distillate thereaction mixture was cooled and agitated with ice and excesshydrochloric acid. The organic layer was separated, washed free of acid,and dried over calcium chloride. After removing the excess diethylcarbonate by distillation, the product. ethyl 3-keto-octanoate,distilled at about 123-126 C. at 19 mm., and the index of refraction wasabout 71. 20/D 1.4333 to. 1.4340. The yield was 61.2 g., or 65% of thetheoretical.

The identity of the product was established by converting a sample toS-n-amyl-l-phenylpyrazoloneby reaction with phenylhydrazine. The

product after recrystallization from 50% alcohol,

melted at 95-96 C.

3-n-amyl-1-p-nitrophenyl-pyrazolone-5 was prepared by combining a sampleof the ester .(1 cc.) with p-nitrophenylhydrazine hydrochlo- 10 ride (1g.) and 50% alcohol (15 ml). 011 standing, the product crystallized andwas purified by recrystallization from 50% alcohol. It melted at 113-1150.

EXAMPLE 1s METHYL NEOPENTYL KETONE Sodium (4.6 g.) was added toanhydrous ethyl alcohol ml.) in a 500 ml., three-necked flask arrangedwith a sealed stirrer, an oil bath and a fractionating column. After thereaction was complete, the excess alcohol Was vacuum distilled out untilonly 25 g. of alcohol remained. The mixture was cooled and diethylcarbonate ml.) was added. The cake of sodium ethylate was broken up bystirring until an even suspension resulted. The mixture was cooled toroom temperature and methyl neopentyl ketone (23 g.) was added withstirring. The mixture was stirred ten minutes and then the bath waswarmed to 50 C. and the sodium ethylate went slowly into solution. Thealcohol present was fractionally distilled out at a bath temperature of100-110 C. and a pressure of 120 mm. during 2.5 hours. The mixture wasthen cooled and worked'up as in Example 12. There was obtained a 66%(24.5 g.) yield of ethyl 3-keto-5,5-dimethylhexanoate, boiling point104-105 C. at 14-15 mm., '7'; 24/D 14333-14335. The product was analyzedand found to contain 64.5% carbon (theory 64.4%) and 10.1% hydrogen(theory 9.7% The product was reacted with 'phenylhydrazine to give asolid derivative, melting at 138-140 C., which was found by assay tocontain 12.1% nitrogen. This compound,3-neopentyl-1-phenyl-pyrazolone-5, has a theoretical nitrogen content of12.2%.

EXAMPLE 19 METHYL N-HEXYL KEIONE Di-n-propyl carbonate (210 g.) andmethyl n-hexyl ketone (48 g.) were placed in a 500 ml., three-neckedflask, fitted with a fractionating column, a dropping funnel, and amechanical stirrer. A solution of potassium propylate, made frompotassium metal (13.5 g.) and n-propyl alcohol ml.), was placed in thedropping funnel. The reaction mixture was brought to refluxing under thecolumn at a pressure of 100 mm. and the solution of po-tassiumpropylatewas added gradually during 3.5 hours. Simultan ously, propyl alcohol wasremoved as distillate at the head of the column at a temperature ofabout 51-54 C. at 100 mm. pressure. When no more propyl alcohol Wasobtainable as distillate the temperature rose rapidly to about 100-102C. at 100 mm. and di-propyl carbonate distilled. The residue was cooled,acidified with acetic acid, agitated with ice water, and the oil wasextracted with ether. The ether extract was dried over calcium chlorideand distilled, yielding n-propyl 3-keto-nonanoate. The product boiled at120-- 122 C. at 3 mm. and its index was n 21/D 1.4370 to 1.4382. Theyield was 52.9 g., or 74% of the theoretical based on methyl n-hexylketone.

Theidentity of the product was established by allowing a sample toreactwith phenylhydrazine, yielding l-phenyl-3-n-hexyl-pyrazolone-5,which melted-at 83-84 C.

EXAMPLE 2o ACETONE cium chloride tube. The flask was cooled in a bath ofacetone and Dry Ice to 45 C., and to the stirred mixture sodiummethylate (54 g.) was slowly added in small portions, Initial additionsof sodium methylate produced an exothermic reaction. It appeared thatthe sodium methylate had caused considerable condensation of theacetone, so more acetone (29 g.) was added. The temperature of reactionwas allowed to rise slowly and at about 15 C. another exothermicreaction was observed, accompanied by a thickening of the reactionmixture.

After standing overnight the mixture was acidified with acetic acid andstirred with ice. The organic layer was separated and the aqueous phasewas extracted with ether and the extract was added to the organic layer.After drying, the ether and diethyl carbonate were carefully strippedoil and the residue was fractionated. Ten fractions were obtained,amounting to 48 g., boiling from 55 at 50 mm. to 120 C. at 2 mm, andvarying progressively from 11. 1'7/D 1.4610 to 1.5251.

It is well known that alkaline agents cause a variety of condensationreactions with acetone, but products containing carboxyl or carbalkoxylgroups are not produced by such condensation reactions.

The fractions described above were therefore subjected to.saponification to determine whether carbalkoxylation had taken place,in addition to the expected condensations. Afraction boiling at 80 to 85C. at 50 mm., of n lfl/D 1.4165, was combined with the next successivefraction, which boiled up to 40 C. at '2 mm., n 17/D 1.4200. Thesaponification equivalent was determined by conventional procedures andwas found to be 221. This indicated that carbalkoxylation had takenplace. The higher boiling fractions also gave evidence ofcarbalkoxylation, but in smaller proportion. Thus, saponificationequivalents of 530 and 604 were found for subsequent fractions.

Carrying out the above carbalkoxylations Without the simultaneousremoval, by distillation, of the alcohols produced in the reactions, isentirely feasible, but the yield is somewhat decreased.

It will be noted that several different procedures are utilized incarrying out the foregoing examples. Any of the procedures employed maybe utilized in carrying out any particular reaction; for example, thedialkyl carbonate and the ketone may be placed in a flask under areflux, and the metal alcoholate gradually dropped in, or the dialkylcarbonate and the alcoholate may be placed in a flask and the ketonedropped in. In either instance, alcohol is preferably taken oiT as adistillate at the head of the column.

The foregoing reactions may be carried out at atmospheric, or underreduced pressure. The selection of operating pressures is determinedmerely by manipulative convenience, in most instances.

In general, it is preferred that the alkyl carbonate and the metalalcoholate shall contain the same alkyl groups in order to be certainthat a mixture of products will not be obtained.

Attention is directed to our copending Patent No. 2,367,632.

[In View of the above it will be seen that the several objects of theinvention are achieved and other advantageous results attained.

As many changes could be made in the above processes and productswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense.

What is claimed is:

1. The method for simultaneously carbalkoxylating andmetallatingacetophenone, which comprises mixing said compound with ananhydrous alcoholate of an alkali metal and a large excess of a dialkylcarbonate over that required as-a reactant.

2. The method for simultaneously carbalkoxylating and imetallatingmethyl neopentyl ketone, which comprises mixing said compound with ananhydrous alcoholate of an alkali metal and a large excess of a dialkylcarbonate over that re-- quired as a reactant.

3. The method for simultaneously carbalkoxylating and metallating methyln-hexyl ketone, which comprises mixing said compound withan anhydrousalcoholate of an alkali metal and a large excess of a dialkyl carbonateover that required as a reactant.

4. A process for simultaneously carbalkoxylating and metallating aketone of the type:

where X is a hydrocarbon'radical, and Y is selected from the groupconsisting of hydrogen and hydrocarbon radicals, which comprises mixingsaid ketone with an anhydrous alkali metal alcoholate and a large excessof a dialkyl carbonate over that required as a reactant, whereby one ofthe hydrogens of the CH2 group is replaced by a carbalkoxyl group andthe other hydrogen is replaced by an alkali metal.

5. A process for simultaneously carbalkoxylating and metallating aketone of the type:

where X is a hydrocarbon radical, and Yis .selected from the groupconsisting of hydrogen and hydrocarbon radicals, which comprises mixingsaid ketone with an anhydrous alcohol-free alkali metal alcoholate, anda dialkyl carbonate in quantity sufficient to function as reagent andreaction medium, whereby one of the hydrogens of the CH2 group isreplaced by a carbalkoxyl group and the other hydrogen is replaced by analkali metal, and removing alcohol.

6. A process for simultaneously carbalkoxylating and metallatin a ketoneof the type:

ing and metallating a ketone of the type:

where X is a hydrocarbon radical, and Y is selected from the groupconsisting of hydrogen and hydrocarbon radicals, which comprises mixingsaid ketone with an anhydrous alkali metal alcoholate and a large excessof a dialkyl carbonate over that required as a reactant, andcontinuously subjecting the mixture to distillation for removing alcoholfrom the reaction mixture,

13 whereby one of the hydrogens of the CH2 group is replaced by acarbalkoxyl group and the other hydrogen is replaced by an alkali metal.

8. A process for simultaneously carbalkoxylating and metallating aketone of the type:

where X is a hydrocarbon radical, and Y is selected from the groupconsisting of hydrogen and hydrocarbon radicals, which comprises mixingsaid ketone with an anhydrous alcohol-free alkali metal alcoholate of alower alcohol and a large excess of a dialkyl carbonate having loweralkyl groups, the quantity of said carbonate being sufficient to providereagent and reaction medium, and continuously subjecting the mixture todistillation for removing alcohol from the reaction mixture, whereby oneof the hydrogens of the CH2 group is replaced by a carbalkoxyl group andthe other hydrogen is replaced by an alkali metal.

9. The method for simultaneously carbalkoxylating and metallatingacetophenone which comprises mixing said compound with anhydrous sodiumethylate and a large excess of diethyl carbonate over that required as areactant.

10. The method for simultaneously carbalkoxylating and metallatingmethyl neopentyl ketone which comprises mixing said compound withanhydrous sodium ethylate and a large excess of diethyl carbonate overthat required as a reactant.

11. The method for simultaneously carbalkoxylating and metallatingmethyl n-hexyl ketone 14 which comprises mixing said compound withanhydrous potassium propylate and a large excess of di-n-propylcarbonate over that required as a reactant.

12. The method for simultaneously carbalkoxylating and metallatingacetophenone which comprises mixing and heating said compound withanhydrous alcohol-free sodium ethylate and a large excess of diethylcarbonate, the quantity thereof being sufiicient to function as reagentand as reaction medium, and continuously subjecting the mixture todistillation for removing alcohol formed by the reaction.

'13. The method for simultaneously carbalkoxylating and metallatingmethyl neopentyl ketone which comprises mixing and heating said compoundwith anhydrous alcohol-free sodium ethylate and a large excess ofdiethyl carbonate, the quantity thereof being sufficient to function asreagent and as reaction medium, and continuously subjecting the mixtureto distillation for removin alcohol formed by the reaction.

14. The method for simultaneously carbalkoxylating and metallatingmethyl n-hexyl ketone which comprises mixing and heating said compoundwith anhydrous alcohol-free potassium propylate and a large excess ofdi-n-propyl carbonate, the quantity thereof being suflicient to functionas reagent and as reaction medium, and continuously subjecting themixture to distillation for removing alcohol formed by the reaction.

VERNON H. WALLINGFORD. AUGUST H. HOIVIEYER.

